transforming-growth-factor-beta and AIDS-Related-Opportunistic-Infections

To characterize changes in serum cytokine levels in human immunodeficiency virus type 1 (HIV-1)-infected persons with Mycobacterium avium complex (MAC) bacteremia, the levels of IL-1alpha (interleukin-1alpha), IL-6, IL-10, tumor necrosis factor alpha (TNF-alpha), soluble type II TNF receptor (sTNF-RII), and transforming growth factor beta (TGF-beta) in serum were measured in two cohorts of HIV-1-infected persons with MAC bacteremia. The first cohort was part of a MAC prophylaxis study. Patients with bacteremia were matched with controls without bacteremia. Elevated IL-6, IL-10, TNF-alpha, sTNF-RII, and TGF-beta levels were noted at baseline for all subjects, a result consistent with advanced HIV-1 disease. IL-1alpha was not detected. No differences in cytokine levels in serum were noted at baseline and at the time of bacteremia between patients with MAC and controls. In the second cohort, subjects had serum samples collected at the time of MAC bacteremia and thereafter while on macrolide therapy. Serum samples at time of bacteremia were collected from HIV-1-infected persons at a time when neither highly active antiretroviral therapy (HAART) nor MAC prophylaxis was used routinely. MAC treatment resulted in decreased levels of IL-6 and TNF-alpha in serum, which were evident for IL-6 by 4 to 6 weeks and for TNF-alpha by 8 to 16 weeks. Thus, antibiotic treatment for MAC results in decreased levels of IL-6 and TNF-alpha in serum in HIV-1-infected persons who are not on HAART.

Topics: AIDS-Related Opportunistic Infections; Anti-Bacterial Agents; Anti-HIV Agents; Antigens, CD; Bacteremia; Case-Control Studies; Cohort Studies; Cytokines; Drug Therapy, Combination; HIV Infections; Humans; Interleukin-10; Interleukin-6; Macrolides; Mycobacterium avium Complex; Mycobacterium avium-intracellulare Infection; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type II; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Cytomegalovirus (CMV) encephalitis is well documented in immunosuppressed persons, but its pathogenesis has received little investigative attention. The examination of brain tissue from 2 patients with acquired immunodeficiency syndrome who had CMV encephalitis showed colocalization of CMV inclusions and transforming growth factor (TGF)-beta in cells that contained astrocyte-specific glial filaments. To investigate the relationship between CMV and TGF-beta in the brain, an ex vivo murine model of CMV-infected astrocytes was established. Cultures of primary murine (strain FVB/N) astrocytes inoculated with murine (Smith strain) CMV expressed, over time, increasing amounts of infectious CMV in parallel with increasing levels of TGF-beta mRNA and peptide. Astrocyte release of CMV declined in the presence of antibody to TGF-beta and increased substantially after the addition of exogenous TGF-beta. These findings suggest that CMV infection of astrocytes induces the production of TGF-beta, which in turn enhances productive CMV expression.

Topics: AIDS-Related Opportunistic Infections; Animals; Astrocytes; Brain; Cells, Cultured; Cytomegalovirus; Cytomegalovirus Infections; Disease Models, Animal; Encephalitis, Viral; HIV-1; Humans; Male; Mice; RNA, Messenger; Transforming Growth Factor beta; Virus Replication

Topics: AIDS-Related Opportunistic Infections; HIV Infections; Humans; Immunocompromised Host; Monocytes; Pneumocystis; Pneumonia, Pneumocystis; Transforming Growth Factor beta; Urokinase-Type Plasminogen Activator

Immune parameters were compared in four groups of Ugandan subjects: HIV-and HIV+ adult patients with active pulmonary TB (HIV- PTB n = 38; HIV+ PTB n = 28), patients with HIV infection only (n = 26) and PPD+ healthy controls (n = 25). Compared with healthy controls, CD4 and CD8 T cells from patients with HIV and/or PTB expressed more activation markers (HLA-DR, CD38); their CD8 T cells expressed more CD95 (pre-apoptosis) and less CD28 (co-stimulatory receptor). Peripheral blood mononuclear cells (PBMC) of patients with either HIV or PTB were impaired in interferon-gamma (IFN-gamma) production upon antigenic stimulation. PTB (with or without HIV) was characterized by monocytosis, granulocytosis, increased transforming growth factor-beta 1 production and PPD-induced apoptosis. In vivo CD4 T cell depletion, in vitro increased spontaneous CD4 T cell apoptosis and defects in IFN-gamma responses upon mitogenic stimulation were restricted to HIV+ subjects (with or without PTB). Overlapping and distinctive immune alterations, associated with PTB and HIV, might explain mutual unfavourable influences of both diseases.

Topics: Adolescent; Adult; AIDS-Related Opportunistic Infections; Apoptosis; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Division; Cells, Cultured; Cytokines; Female; Humans; Interferon-gamma; Leukocytes, Mononuclear; Lymphocyte Activation; Male; Middle Aged; Mitogens; Pokeweed Mitogens; Sputum; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tuberculin; Tuberculosis, Pulmonary; Tumor Necrosis Factor-alpha; Uganda

Local cellular immune responses may affect presentation and outcome in tuberculosis (TB). To investigate this hypothesis, we performed bronchoalveolar lavage (BAL) on 30 patients with untreated pulmonary tuberculosis and assessed the type of cellular inflammatory response and cytokine production. We then correlated BAL findings and cytokine production with clinical findings. We also performed BAL on a subset of patients to examine changes in cytokine production by BAL cells over time. We found that at presentation patients with less clinically and radiographically advanced TB (smear-negative, noncavitary disease) had a local immune response characterized by a predominance of lymphocytes. Furthermore, BAL cells from these patients secreted interferon (IFNgamma), and not Interleukin-4, suggesting a Th 1-type lymphocytic response. In patients with smear-positive and/or cavitary disease, macrophages or polymorphonuclear leukocytes were the predominant BAL cell type, but with treatment and clinical improvement these patients went on to recruit IFNgamma producing cells to the lung. We conclude that the type of cellular immune response that occurs locally in the lung may affect presentation and outcome in pulmonary TB, and an understanding of the development of this response may lead to insights into pathogenesis and novel therapies for TB.

Topics: Adult; Aged; AIDS-Related Opportunistic Infections; Antitubercular Agents; Bronchoalveolar Lavage Fluid; Cell Movement; Cytokines; Female; Follow-Up Studies; Humans; Immunity, Cellular; Interferon-gamma; Interleukin-1; Interleukin-4; Lung; Lymphocytes; Macrophages; Male; Middle Aged; Neutrophils; Radiography; Th1 Cells; Transforming Growth Factor beta; Treatment Outcome; Tuberculosis, Pulmonary; Tumor Necrosis Factor-alpha

We have compared the phenotypic and functional changes found in alveolar macrophages recovered from the lungs of 39 HIV-positive individuals with no respiratory disease with those from 33 HIV-positive individuals with pneumonitis and 31 healthy controls.. Bronchoalveolar lavage (BAL) cell cytospin preparations were stained using monoclonal antibody immunoperoxidase and double immunofluorescence techniques. Cytokine levels within supernatant BAL were determined using enzyme immunoassay.. There were marked differences in alveolar macrophage phenotype between the three groups. In particular, the relative proportion of cells staining RFD1+RFD7- (inducer cells) was reduced in the HIV-positive individuals without respiratory disease. This was correlated with measures of declining systemic immunity. Patients with pneumonitis had the highest levels of measured cytokines [interleukin-1 beta, tumour necrosis factor-alpha and transforming growth factor (TGF)-beta 2], followed by the HIV-positive individuals without respiratory disease. In this latter population a negative correlation was found between active (non acid dissociated) TGF-beta 2 and blood CD4 cell count.. The differences between the three groups suggest that alterations of potential relevance to the pulmonary immune response are occurring in alveolar macrophages prior to the onset of respiratory disease. This study confirms the importance of investigating asymptomatic HIV-positive individuals.

Topics: AIDS-Related Opportunistic Infections; Antigens, CD; Antigens, Differentiation, Myelomonocytic; beta 2-Microglobulin; CD4 Lymphocyte Count; Cell Count; Female; HLA-DR Antigens; Humans; Interleukin-1; Lipopolysaccharide Receptors; Macrophages, Alveolar; Male; Phenotype; Pneumonia; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Topics: AIDS-Related Opportunistic Infections; Biopsy; Culture Techniques; HIV Infections; HIV-1; Humans; Jejunum; Transforming Growth Factor beta

We examined the interaction between HIV-1 Tat protein and the opportunistic pathogen Mycobacterium avium. AIDS-associated strains of M. avium were shown to bind Tat protein quite avidly in an attachment assay. The attachment of M. avium to Tat was shown to occur via the integrin alpha 5 beta 1 present on the mycobacterial cell surface. M. avium strains were shown to bind the viral Tat protein with high affinity in a specific fashion (600 binding sites with a Kd of 1 to 5 nM). M. avium coated with Tat protein were shown to be more infective for human alveolar macrophages than untreated M. avium. Other HIV-1 Ags had no such effects (e.g., p24, p17). Examination of the cytokine profile of infected macrophages showed that M. avium-Tat complexes induced higher levels of TGF beta-1 (TGF beta 1) than M. avium alone or M. avium that had been in contact with other viral proteins. Conditioned media from HIV-1-infected H9 cells released a factor that enhanced M. avium intramacrophage growth, and was partially neutralized by an anti-Tat Ab. Finally, Tat protein (purified or present in conditioned media from infected cells) moderately enhanced the growth of M. avium strains in extracellular media, and exposure of M. avium to Tat protein in the presence of IL-6 enhanced the growth of AIDS-associated strains. These data argue for an interaction between the Tat viral product and the opportunistic pathogen M. avium which may contribute to the exquisite susceptibility of AIDS subjects to this pathogen.

Topics: Acquired Immunodeficiency Syndrome; AIDS-Related Opportunistic Infections; Bacterial Adhesion; Gene Products, tat; HIV-1; Humans; Integrins; Interleukin-6; Macrophages, Alveolar; Monokines; Mycobacterium avium; tat Gene Products, Human Immunodeficiency Virus; Transforming Growth Factor beta